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Ro 32-0432, a selective and orally active inhibitor of protein kinase C prevents T-cell activation.

Abstract
Several lines of circumstantial evidence support the assumption that protein kinase C (PKC) activation together with elevated levels of cytosolic Ca++ are necessary for T-cell activation and proliferation in response to a physiological stimulus, i.e., MHC class II restricted antigen presentation. By using a potent, cell-permeable and selective inhibitor of PKC, Ro 32-0432, we have tested this hypothesis. Ro 32-0432 inhibits interleukin-2 (IL-2) secretion, IL-2 receptor expression in, and proliferation of, peripheral human T-cells stimulated with phorbol ester together with phytohemagglutin or anti-CD3, but does not inhibit IL-2 induced proliferation in cells already stimulated to express IL-2 receptors. Proliferation of the influenza peptide antigen HA 307-319-specific human T-cell clone (HA27) after exposure to antigen-pulsed autologous presenting cells was also inhibited by Ro 32-0432. Oral administration of Ro 32-0432 inhibited subsequent phorbol ester-induced edema in rats demonstrating the systemic efficacy of the compound to inhibit PKC-driven responses. Induction of more physiologically T-cell driven responses such as host vs. graft responses and the secondary paw swelling in adjuvant-induced arthritis were also inhibited by Ro 32-0432. These data demonstrate the crucial role for PKC in T-cell activation and that selective p.o. bioavailable PKC inhibitors are efficacious in preventing T-cell driven chronic inflammatory responses in vivo. Inhibition of PKC represents an important mechanistic approach to prevent T-cell activation and compounds of this class may have important therapeutic applicability to chronic inflammatory and autoimmune diseases.
AuthorsA M Birchall, J Bishop, D Bradshaw, A Cline, J Coffey, L H Elliott, V M Gibson, A Greenham, T J Hallam, W Harris
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 268 Issue 2 Pg. 922-9 (Feb 1994) ISSN: 0022-3565 [Print] United States
PMID8114006 (Publication Type: Journal Article)
Chemical References
  • Indoles
  • Pyrroles
  • Ro 32-0432
  • Phorbol 12,13-Dibutyrate
  • Protein Kinase C
Topics
  • Administration, Oral
  • Amino Acid Sequence
  • Animals
  • Arthritis, Experimental (prevention & control)
  • Female
  • Indoles (pharmacology)
  • Lymphocyte Activation (drug effects)
  • Male
  • Mice
  • Molecular Sequence Data
  • Phorbol 12,13-Dibutyrate (pharmacology)
  • Protein Kinase C (antagonists & inhibitors)
  • Pyrroles (pharmacology)
  • Rats
  • Rats, Inbred Lew
  • T-Lymphocytes (drug effects, immunology)

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